Anaesthetic composition

ABSTRACT

The compound 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether, processes for its manufacture, compositions containing it and its use as an inhalation anaesthetic.

This is a division of application Ser. No. 637,680, filed Dec. 4, 1975,now U.S. Pat. No. 4,080,389.

This invention relates to a novel halogenated ether which possessesanaesthetic activity and which is substantially free from undesirableside-effects when administered to warm-blooded animals by inhalation.

According to the present invention there is provided the novel compound2-chloro-1,2,2-trifluoroethyl difluoromethyl ether having the formulaCHF₂ OCHFCClF₂.

The structure of the compound is confirmed by the following physicaldata:

    ______________________________________                                        Mass spectrum: principal ions                                                 m/e          % intensity  ion                                                 ______________________________________                                        149           2           CHF.sub.2 OCHFCF.sub.2                              117/119      13/4         C.sub.2 F.sub.3 HCl                                 101          10           C.sub.2 F.sub.4 O                                   99           10           C.sub.2 F.sub.3 H.sub.2 O                           85/87         4/1         CF.sub.2 Cl                                         71            8           CF.sub.2 H.sub.2                                    67/69        13/4         CHClF                                               51           100          CHF.sub.2                                           29           78           CHO                                                 ______________________________________                                    

    ______________________________________                                        Proton magnetic resonance spectrum (in carbon                                 tetrachloride using tetramethylsilane as internal                             reference)                                                                    δ                                                                       ______________________________________                                        5.83         doublet of triplets                                                                            --CHF--                                         6.4          triplet          --CHF.sub.2                                     ______________________________________                                    

    ______________________________________                                        F.sup.19 magnetic resonance spectrum (in CFCl.sub.3)                          ______________________________________                                        140.7 ppm     doublet of multiplets                                                                          --CHF--                                        86.2 ppm      doublet AB system                                                                              --CHF.sub.2                                    72.0 ppm      doublet of doublets                                                                            --CF.sub.2 Cl                                  ______________________________________                                    

The compound has a boiling point of 56° C. at normal atmosphericpressure.

According to a further feature of the invention there is provided aprocess for the manufacture of 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether which comprises either the chlorination ofdifluoromethyl 1,2,2-trifluoroethyl ether (CHF₂ OCHFCHF₂) or thefluorination of methyl 2,2,2-trichloroethyl ether (CH₃ OCH₂ CCl₃).

The chlorination process may conveniently be carried out at a laboratorytemperature using gaseous chlorine under the influence of ultravioletradiation. The fluorination process may conveniently be carried outusing a high-valency metal fluorinating agent, for example cobalticfluoride, at an elevated temperature, for example at 60° C.

The CHF₂ OCHFCHF₂ used as starting material is a known compound(Tetrahedron, 1971, 27, 4533 to 4551). The CH₃ OCH₂ CCl₃ used asstarting material is a known compound (Bulletin de la Societe Chimiquede France 1967, 1520-1532).

According to a further feature of the invention there is provided aninhalation anaesthetic composition which comprises as anaesthetic agent2-chloro-1,2,2-trifluoroethyl difluoromethyl ether together with oxygenand optionally together with one or more otherphysiologically-acceptable material(s), the proportion of anaestheticagent in the composition being such that when the composition isadministered by inhalation to a warm-blooded animal anaesthesia isproduced and/or maintained, and the proportion of oxygen in thecomposition being such that when the composition is administered byinhalation to a warm-blooded animal respiration is maintained.

It is to be understood that the 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether must be free of toxic impurities when it is used inthe composition of the invention.

The oxygen present in the composition of the invention may be pureoxygen, or it may be in the form of air, that is in a mixture withnitrogen and smaller quantities of other gases.

The other physiologically-acceptable material(s) that may optionally bepresent in the composition of the invention may be, for example, one ormore substances selected from other inhalant anaesthetics, for examplehalothane, nitrous oxide, diethyl ether, divinyl ether, trifluoroethylvinyl ether, cyclopropane, trichloroethylene, chloroform, enflurane,fluroxene, methoxyflurane, teflurane and 1-chloro-2,2,2-trifluoroethyldifluoromethyl ether; pharmaceutically-inert gases, for examplenitrogen, chemically inert gases such as are present in air, for exampleneon and argon, and carbon dioxide and water vapour; andpharmaceutically-acceptable stabilisers which may be present to protectone or more of the other components of the composition from the effectof light, oxidation and/or attack by acid or base. As a suitablestabiliser there may be used, for example, a volatile stabilising agentwhich is physiologically tolerable, for example ethanol, or anon-volatile stabilising agent which is not carried over substantiallyduring vaporisation, for example thymol.

The composition of the invention will usually contain between 0.25% and3.5% volume by volume of the 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether.

The composition of the invention may be administered to warm-bloodedanimals, including man, for the production of anaesthesia byconventional techniques. The composition may be preformed andadministered as such, or alternatively the 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether and oxygen, either of which may have otherphysiologically-acceptable materials present with it, may beadministered separately, the composition of the invention being formedeither immediately prior to, or during, the course of administration.For example, the composition may be used in apparatus or machinesadapted for the vaporisation of liquid anaesthetics and the admixturethereof with oxygen or with air or other gaseous mixtures containingoxygen in amount capable of supporting respiration.

According to a further feature of the invention there is provided aninhalation anaesthetic apparatus charged with2-chloro-1,2,2-trifluoroethyl difluoromethyl ether.

According to a further feature of the invention there is provided amethod for producing anaesthesia in a warm-blooded animal whichcomprises administering to said animal an anaesthetically-effectiveamount of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether togetherwith sufficient oxygen to maintain respiration.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1

Chlorine gas was bubbled during 4 hours at a rate of 40 ml./minutethrough 40 ml. (57 g.) of difluoromethyl 1,2,2-trifluoroethyl ether(CHF₂ OCHFCHF₂) under ultraviolet irradiation. Unreacted chlorine passedfrom the reaction vessel through a vertical air condenser and a dephleg,maintained at -78° C. with trichloroethylene/solid carbon dioxide, whichcondensed any organic components of the exit gases. The reaction mixturewas then distilled into a cold trap, dried over a molecular sieve andfinally separated into its components on a preparative gas-liquidchromatogram using a 30 ft. column containing 20% by weight of diethylhexyl sebacate supported on `Celite` (Registered Trade Mark).

2-Chloro-1,2,2-trifluoroethyl difluoromethyl ether was obtained in about6% yield based on difluoromethyl 1,2,2-trifluoroethyl ether.

EXAMPLE 2

Methyl 2,2,2-trichloroethyl ether (56 ml.) was added during 5 hours to areactor containing cobalt (III) fluoride (2000 g.) which was stirred andmaintained at 60° C. Nitrogen was then blown through the stirred reactorcontents for 1 hour, the material entrained by the nitrogen beingcondensed and collected in a trap maintained at -75° C. The contents ofthe trap were washed with water and dried over molecular sieve, 45 g. ofmaterial being produced.

The combined product from ten such reactions was fractionally distilledand the desired fraction further purified by gas chromatography using a30 ft. × 0.5 inch column containing 20% by weight of a polyethyleneglycol (`Carbowax` M; Registered Trade Mark) supported on `Celite`.There was thus obtained 2-chloro-1,2,2-trifluoroethyl difluoromethylether (120 g.).

EXAMPLE 3

A group of 6 mice is placed in a chamber of 10 liters capacity whichcontains solid soda lime, and a mixture of 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether and oxygen, of known percentage, is released intothe chamber. A reservoir bag containing the known percentage mixture isused to maintain atmospheric pressure as the mixture is inhaled by themice and as exhaled carbon dioxide is absorbed by the soda lime. After30 minutes the concentration of 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether in the chamber is determined by gas chromatography.

The experiment is repeated using different mixtures of2-chloro-1,2,2-trifluoroethyl difluoromethyl ether and oxygen, and theAC₅₀, that is the concentration by volume of2-chloro-1,2,2-trifluoroethyl difluoromethyl ether which anaesthetises 3mice out of 6 after 30 minutes exposure, is found to be 0.9%. The LC₅₀,that is the concentration by volume of 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether which kills 3 mice out of 6 after 30 minutesexposure, is found to be 4.2%. The therapeutic ratio of the compound istherefore 4.2/0.9, that is 4.7. Under similar conditions the AC₅₀, LC₅₀and therapeutic ratio for halothane are respectively 0.85%, 3.4% and4.0.

EXAMPLE 4

A mixture of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether (3% v/v)and air (97% v/v) was administered to a cat for a period of 10 minutes.Induction of anaesthesia and subsequent recovery from anaesthesia weresmooth, and rapid.

EXAMPLE 5

A cat was anaesthetised by injection of a 2.5% w/v solution ofthiopentone sodium in water into a cephalic vein at a dose equivalent to20 mg./kg. bodyweight. Anaesthesia was subsequently maintained byadministration of a mixture of 2-chloro-1,2,2-trifluoroethyldifluoromethyl ether (1% v/v) and oxygen (99% v/v) contained in a largenylon reservoir bag. Aanesthesia was maintained in this way for 40minutes. Mean arterial pressure and heart rate during this period wereboth substantially higher than under comparable anaesthesia withhalothane.

What we claim is:
 1. An inhalation anaesthetic composition whichcomprises as anaesthetic agent an anaesthetically effective amount of2-chloro-1,2,2-trifluoroethyl difluoromethyl ether together with oxygen,the proportion of anaesthetic agent in the composition being such thatwhen the composition is administered by inhalation to a warm-bloodedanimal anaesthesia is produced or maintained, and the proportion ofoxygen in the composition being such that when the composition isadministered by inhalation to a warm-blooded animal respiration ismaintained.
 2. A composition as claimed in claim 1 which containsbetween 0.25% and 3.5% volume by volume of the2-chloro-1,2,2-trifluoroethyl difluoromethyl ether.
 3. A method forproducing anaesthesia in a warm-blooded animal which comprisesadministering by inhalation to said animal an anaesthetically-effectiveamount of 2-chloro-1,2,2-trifluoroethyl difluoromethyl ether togetherwith sufficient oxygen to maintain respiration.